The double life of MULE in preeclamptic and IUGR placentae

Area of Science:

• Reproductive Biology
• Molecular Biology
• Cellular Biology

Background:

• Mcl-1 and p53 are crucial for trophoblast cell survival and death.
• Mechanisms regulating Mcl-1 and p53 in human placental development are not fully understood.
• MULE (Mcl-1 Ubiquitin Ligases E3) is an E3 ubiquitin ligase targeting Mcl-1 and p53 for degradation.

Purpose of the Study:

• To investigate MULE's role in Mcl-1 and p53 degradation during normal and abnormal placental development.
• To determine the influence of oxygen tension on MULE expression and activity.
• To elucidate the distinct molecular mechanisms in preeclampsia (PE) and intrauterine growth restriction (IUGR) involving MULE.

Main Methods:

• Quantification of MULE, Mcl-1, and p53 expression in placental tissues across gestation and in PE/IUGR.
• In vitro studies using first-trimester villous explants and JEG3 choriocarcinoma cells.
• Oxygen exposure experiments (3% vs. 20% O2) and hypoxia-inducible factor (HIF)-1α knockdown (siRNA).
• Analysis of MULE binding, ubiquitination of Mcl-1 and p53.

Main Results:

• MULE expression peaked early in gestation (5-7 weeks) and inversely correlated with Mcl-1 and p53 levels.
• Low oxygen (3% O2) increased MULE expression, mediated by HIF-1α.
• MULE was overexpressed in both PE and IUGR placentae.
• In PE, MULE targeted p53, leading to Mcl-1 isoform accumulation.
• In IUGR, MULE targeted Mcl-1, allowing p53 accumulation.

Conclusions:

• Oxygen regulates Mcl-1 and p53 stability in the placenta via HIF-1-controlled MULE expression.
• MULE plays distinct roles in PE and IUGR by differentially targeting p53 and Mcl-1.
• These findings classify early-onset PE and IUGR as distinct molecular pathologies based on MULE's substrate preference.